12-11650161-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1 PM2 PP3_Strong PP5

The NM_001987.5(ETV6):c.33+1G>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ETV6 NM_001987.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.42

Genes affected

ETV6 (HGNC:3495): (ETS variant transcription factor 6) This gene encodes an ETS family transcription factor. The product of this gene contains two functional domains: a N-terminal pointed (PNT) domain that is involved in protein-protein interactions with itself and other proteins, and a C-terminal DNA-binding domain. Gene knockout studies in mice suggest that it is required for hematopoiesis and maintenance of the developing vascular network. This gene is known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-11650161-G-A is Pathogenic according to our data. Variant chr12-11650161-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2574037.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETV6	NM_001987.5	c.33+1G>A		splice_donor_variant		ENST00000396373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETV6	ENST00000396373.9	c.33+1G>A		splice_donor_variant		1	NM_001987.5	P1
ETV6	ENST00000541426.1	n.217+1G>A		splice_donor_variant, non_coding_transcript_variant		4
ETV6	ENST00000544715.1	n.150+1G>A		splice_donor_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant lymphoma, large B-cell, diffuse Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Wasik Lab, Fox Chase Cancer Center

Jul 25, 2023

This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. ETV6 is a transcription factor with a critical role in hematopoiesis and embryonic development, frequently mutated in hematologic malignancies. ETV6 c.33+1G>A was present at initial presentation, but was not detected in relapsed tumor. This variant changes a consensus splice donor site and is expected to affect protein structure. Although alterations in ETV6 are one of the hallmark features of the MCD/C5 group, its oncogenic role in DLBCL remains undefined (Marino et al. 2022). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	34
Dann	Benign	0.97
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Benign	0.28	N
MutationTaster	Benign	1.0	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -41
DS_DL_spliceai		0.94		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-11803095; COSMIC: COSV67148243;